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Abstract The randomized, phase 2 GRIFFIN study (NCT02874742) evaluated daratumumab plus lenalidomide/bortezomib/dexamethasone (D-RVd) in transplant-eligible newly diagnosed multiple myeloma (NDMM). We present final post hoc analyses (median follow-up, 49.6 months) of clinically relevant subgroups, including patients with high-risk cytogenetic abnormalities (HRCAs) per revised definition (del[17p], t[4;14], t[14;16], t[14;20], and/or gain/amp[1q21]). Patients received 4 induction cycles (D-RVd/RVd), high-dose therapy/transplant, 2 consolidation cycles (D-RVd/RVd), and lenalidomide±daratumumab maintenance (≤ 2 years). Minimal residual disease–negativity (10−5) rates were higher for D-RVd versus RVd in patients ≥ 65 years (67.9% vs 17.9%), with HRCAs (54.8% vs 32.4%), and with gain/amp(1q21) (61.8% vs 28.6%). D-RVd showed a trend toward improved progression-free survival versus RVd (hazard ratio [95% confidence interval]) in patients ≥ 65 years (0.29 [0.06–1.48]), with HRCAs (0.38 [0.14–1.01]), and with gain/amp(1q21) (0.42 [0.14–1.27]). In the functional high-risk subgroup (not MRD negative at the end of consolidation), the hazard ratio was 0.82 (0.35–1.89). Among patients ≥ 65 years, grade 3/4 treatment-emergent adverse event (TEAE) rates were higher for D-RVd versus RVd (88.9% vs 77.8%), as were TEAEs leading to discontinuation of ≥ 1 treatment component (37.0% vs 25.9%). One D-RVd patient died due to an unrelated TEAE. These results support the addition of daratumumab to RVd in transplant-eligible patients with high-risk NDMM. Video Abstract

Abstract Background Low skeletal muscle mass (LSMM) and/or, function associated with an increased risk of treatment‐related toxicities and inferior overall survival (OS) among adults with solid malignancies. However, the association between LSMM and treatment‐related toxicities among adults with haematologic malignancies remains unclear. Methods Using a pre‐published protocol (CRD42020197814), we searched seven bibliographic databases from inception to 08/2021 for studies reporting the impact of LSMM among adults ≥18 years with a known haematologic malignancy. The primary outcome of interest was OS, and secondary outcomes included progression free survival (PFS) and non‐relapse mortality (NRM). These effect sizes were quantified in terms of hazards ratio (HR) along with 95% confidence interval (CI) and pooled across studies using a DerSimonian–Laird random‐effects model. Heterogeneity was assessed using the Cochran's Q and the I2 statistic. All hypothesis testing was two‐sided with an alpha of 0.05. Results Of 3791 studies screened, we identified 20 studies involving 3468 patients with a mean age of 60 years; 44% were female and the most common malignancy was diffuse large B‐cell lymphoma (42%). Most studies measured muscle mass using single slice computed tomography imaging at the L3 level. The presence of LSMM was associated with worse OS (pooled HR = 1.81, 95% CI = 1.48–2.22, P

Abstract In the MASTER study (NCT03224507), daratumumab+carfilzomib/lenalidomide/dexamethasone (D-KRd) demonstrated promising efficacy in transplant-eligible newly diagnosed multiple myeloma (NDMM). In GRIFFIN (NCT02874742), daratumumab+lenalidomide/bortezomib/dexamethasone (D-RVd) improved outcomes for transplant-eligible NDMM. Here, we present a post hoc analysis of patients with high-risk cytogenetic abnormalities (HRCAs; del[17p], t[4;14], t[14;16], t[14;20], or gain/amp[1q21]). Among 123 D-KRd patients, 43.1%, 37.4%, and 19.5% had 0, 1, or ≥2 HRCAs. Among 120 D-RVd patients, 55.8%, 28.3%, and 10.8% had 0, 1, or ≥2 HRCAs. Rates of complete response or better (best on study) for 0, 1, or ≥2 HRCAs were 90.6%, 89.1%, and 70.8% for D-KRd, and 90.9%, 78.8%, and 61.5% for D-RVd. At median follow-up (MASTER, 31.1 months; GRIFFIN, 49.6 months for randomized patients/59.5 months for safety run-in patients), MRD-negativity rates as assessed by next-generation sequencing (10–5) were 80.0%, 86.4%, and 83.3% for 0, 1, or ≥2 HRCAs for D-KRd, and 76.1%, 55.9%, and 61.5% for D-RVd. PFS was similar between studies and superior for 0 or 1 versus ≥2 HRCAs: 36-month PFS rates for D-KRd were 89.9%, 86.2%, and 52.4%, and 96.7%, 90.5%, and 53.5% for D-RVd. These data support the use of daratumumab-containing regimens for transplant-eligible NDMM with HCRAs; however, additional strategies are needed for ultra-high–risk disease (≥2 HRCAs). Video Abstract

Abstract Extra copies of chromosome 1q21 (+1q: gain = 3 copies, amp >= 4 copies) are associated with worse outcomes in multiple myeloma (MM). This systematic review assesses the current reporting trends of +1q, the efficacy of existing regimens on +1q, and its prognostic implications in MM randomized controlled trials (RCTs). Pubmed, Embase and Cochrane Registry of RCTs were searched from January 2012 to December 2022. Only MM RCTs were included. A total of 124 RCTs were included, of which 29 (23%) studies reported on +1q. Among them, 10% defined thresholds for +1q, 14% reported survival data separately for gain and amp, and 79% considered +1q a high-risk cytogenetic abnormality. Amongst RCTs that met the primary endpoint showing improvement in progression free survival (PFS), lenalidomide maintenance (Myeloma XI), selinexor (BOSTON), and isatuximab (IKEMA and ICARIA) were shown to improve PFS for patients with evidence of +1q. Some additional RCT’s such as Myeloma XI+ (carfilzomib), ELOQUENT-3 (elotuzumab), and HOVON-65/GMMG-HD4 (bortezomib) met their endpoint showing improvement in PFS and also showed improvement in PFS in the +1q cohort, although the confidence interval crossed 1. All six studies that reported HR for +1q patients vs. without (across both arms) showed worse OS and PFS for +1q. There is considerable heterogeneity in the reporting of +1q. All interventions that have shown to be successful in RCTs and have clearly reported on the +1q subgroup have shown concordant direction of results and benefit of the applied intervention. A more standardized approach to reporting this abnormality is needed.

Abstract Quadruplet induction, autologous hematopoietic cell transplant (AHCT), and measurable residual disease (MRD) response‐adapted consolidation yield an unprecedented depth of response in newly diagnosed multiple myeloma. Patients treated on MASTER (NCT03224507) ceased therapy and entered active surveillance (MRD‐SURE) after achieving MRD negativity. This study characterizes quantitative changes in the immunoglobulin (Ig) gene repertoire by next‐generation sequencing and serum gamma globulin levels. Quadruplet therapy leads to profound hypogammaglobulinemia and reduction in the Ig gene repertoire. Immune reconstitution (IR) is delayed in patients who received post‐AHCT consolidation compared to those who do not. Eighteen months after treatment cessation, there was no statistically significant difference between the groups.

Abstract There are disparities in outcomes for patients with multiple myeloma (MM). We evaluated the influence of sociodemographic factors on global disparities in outcomes for patients with MM. This rapid evidence assessment (PROSPERO, CRD42021248461) followed PRISMA-P guidelines and used the PICOS framework. PubMed and Embase® were searched for articles in English from 2011 to 2021. The title, abstract, and full text of articles were screened according to inclusion/exclusion criteria. The sociodemographic factors assessed were age, sex, race/ethnicity, socioeconomic status, and geographic location. Outcomes were diagnosis, access to treatment, and patient outcomes. Of 84 articles included, 48 were US-based. Worldwide, increasing age and low socioeconomic status were associated with worse patient outcomes. In the US, men typically had worse outcomes than women, although women had poorer access to treatment, as did Black, Asian, and Hispanic patients. No consistent disparities due to sex were seen outside the US, and for most factors and outcomes, no consistent disparities could be identified globally. Too few studies examined disparities in diagnosis to draw firm conclusions. This first systematic analysis of health disparities in patients with MM identified specific populations affected, highlighting a need for additional research focused on assessing patterns, trends, and underlying drivers of disparities in MM.

The impact of nonbiological factors (NBF) on survival was investigated in a large cohort of adolescents and young adults (AYA) with lymphoma in the United States (US). We found that uninsured and Medicaid AYA beneficiaries with classical Hodgkin lymphoma (cHL) and non-Hodgkin lymphoma (NHL) are at significantly increased risk of death when compared with their insured counterpart even after adjustment for other factors affecting survival. Increased risk of death was also noted for Non-Hispanic Black (NHB) patients with cHL and NHL when compared to Non-Hispanic White (NHW) patients, however, only Hispanic patients with NHL were found to have a significantly increased mortality risk while those with cHL were not. NHL AYA patients residing in lower-income counties are at increased risk of death. The strong association of NBF with survival indicates opportunities to improve the survival of AYA lymphoma patients by improving access/quality of care in the US.

Multiple myeloma (MM) remains incurable, and treatment of relapsed/refractory (R/R) disease is challenging. There is an unmet need for more targeted therapies in this setting; deep cellular and molecular phenotyping of the tumor and microenvironment in MM could help guide such therapies. This phase 1b study (NCT02431208) evaluated the safety and efficacy of the anti-programmed death-ligand 1 monoclonal antibody atezolizumab (Atezo) alone or in combination with the standard of care (SoC) treatments lenalidomide (Len) or pomalidomide (Pom) and/or daratumumab (Dara) in patients with R/R MM. Study endpoints included incidence of adverse events (AEs) and overall response rate (ORR). A novel unsupervised integrative multi-omic analysis was performed using RNA sequencing, mass cytometry immunophenotyping, and proteomic profiling of baseline and on-treatment bone marrow samples from patients receiving Atezo monotherapy or Atezo+Dara. A similarity network fusion (SNF) algorithm was applied to preprocessed data. Eighty-five patients were enrolled. Treatment-emergent deaths occurred in 2 patients; both deaths were considered unrelated to study treatment. ORRs ranged from 11.1% (Atezo+Len cohorts, n=18) to 83.3% (Atezo+Dara+Pom cohort, n=6). High-dimensional multi-omic profiling of the tumor microenvironment and integrative SNF analysis revealed novel correlations between cellular and molecular features of the tumor and immune microenvironment, patient selection criteria, and clinical outcome. Atezo monotherapy and SoC combinations were safe in this patient population and demonstrated some evidence of clinical efficacy. Integrative analysis of high dimensional genomics and immune data identified novel clinical correlations that may inform patient selection criteria and outcome assessment in future immunotherapy studies for myeloma.

Abstract Background Population‐based studies previously showed an improvement in overall survival (OS) for patients with diffuse large B‐cell lymphoma (DLBCL) who received chemoimmunotherapy with rituximab. However, there is limited data (especially at the population level) that show a similar trend in OS improvement, in the most recent time period. We hypothesized that survival for DLBCL patients diagnosed in the United States has continued to improve in recent years and intended to measure outcome improvements. Methods Using the SEER‐18 registries, we compared the incidence and relative survival rates (RSRs) of DLBCL patients between 2002‐2007 and 2008‐2013 (availability of novel agents, broader use of autologous hematopoietic cell transplantation and improvement in supportive care). Multivariable Cox regression models were used to assess associations between the year of diagnosis and OS while controlling for age, gender, stage, and ethnicity. Results There were a total of 53 439 patients with DLBCL who were diagnosed between 2002 and 2013. Of these, 25 810 were diagnosed during time period‐1 and 27 629 diagnosed during time period‐2. There was a slight decline in incidence of DLBCL (time period‐1 vs time period‐2), 7.75 (95% CI = 7.66‐7.84) vs 7.43 (95% CI = 7.34‐7.52) cases per 100 000 persons, respectively (P

We present the case of a 24-year-old male, who received a minor ABO-incompatible allogeneic hematopoietic stem cell transplant (HSCT, blood group O+ ⟶ A+) from an HLA-matched unrelated female donor, as consolidation therapy for relapsed precursor-B-cell acute lymphoblastic leukemia. The donor had a known history of Hashimoto’s thyroiditis before HSCT. At day +10 posttransplant, the patient developed severe hemolysis, which required emergent red blood cell exchange. Additionally, about a year posttransplant, he had circulating antithyroglobulin antibodies, decreased free-T4 (fT4) and increased serum thyroid-stimulating hormone (TSH). The potential causes of the posttransplant hemolytic episode and hypothyroidism are discussed. While the hemolysis was worsened by the transfusion of A red blood cells (RBCs) in the context of passenger lymphocyte syndrome, the thyroid dysfunction might be explained by an autoimmune disease transferred from the donor. The case highlights the possibility of several non-relapse-related complications of HSCT occurring in the same patient. It is critical that such adverse outcomes are distinguished from classical graft-versus-host disease (GVHD) for adequate recipient counseling, posttransplant screening, and prompt treatment.

Extraordinary progress has been made over the last decade in the treatment of multiple myeloma with the incorporation of new drugs, particularly proteasome inhibitors, immunomodulators, and monoclonal antibodies.The combined use of innovative drugs, already in the first lines of treatment, has led to an expressive increase in the survival of these patients. However, the approach to relapse remains a great challenge, and the disease continues to be incurable. In this scenario, modern immunotherapy has gained the limelight, especially with its recent use of CAR-T cells in clinical trials, as in the case of multiple myeloma, having the BCMA as the primary target.The results are impactful in the treatment of multiple myeloma patients who have had multiple relapses and are triple- and penta-refractory. In this Consensus, we have brought together a group of experts in multiple myeloma to discuss and forward their recommendations for the future, which we hope is very near, incorporating the CAR-T in our country.

Chimeric antigen receptor T-cells (CAR-T cells) are a new modality of oncological treatment which has demonstrated impressive response in refractory or relapsed diseases, such as acute lymphoblastic leukemia (ALL), lymphomas, and myeloma but is also associated with unique and potentially life-threatening toxicities. The most common adverse events (AEs) include cytokine release syndrome (CRS), neurological toxicities, such as the immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenias, infections, and hypogammaglobulinemia. These may be severe and require admission of the patient to an intensive care unit. However, these AEs are manageable when recognized early and treated by a duly trained team. The objective of this article is to report a consensus compiled by specialists in the fields of oncohematology, bone marrow transplantation, and cellular therapy describing recommendations on the Clinical Centers preparation, training of teams that will use CAR-T cells, and leading clinical questions as to their use and the management of potential complications.

Abstract: Prior improvements in multiple myeloma (MM) survival were not fully observed in racial and ethnic minorities and older individuals. We hypothesized that improvements in MM management in recent years have reduced these disparities. We used the Surveillance, Epidemiology, and End Results registries to calculate the incidence and relative survival rates (RSRs) of MM in the United States for patients diagnosed from 1993 to 1997 (prethalidomide), 1998 to 2002 (introduction of thalidomide), 2003 to 2007 (bortezomib and lenalidomide), and 2008 to 2012 (upfront bortezomib and lenalidomide, early availability of carfilzomib and pomalidomide). MM incidence increased significantly among non-Hispanic whites (NHWs) and non-Hispanic black (NHB) men, but not among NHB women and Hispanics. Improvement in 5-year RSRs (1993-1997 vs 2008-2012) was seen among patients of all age and race/ethnicity groups. Ten-year RSRs (1993-1997 vs 2003-2007) improved for patients

Initial therapy of chronic graft-versus-host disease is prednisone ± a calcineurin-inhibitor, but most patients respond inadequately. In a randomized, adaptive, phase II/III, multicenter trial we studied whether prednisone/sirolimus or prednisone/sirolimus/photopheresis was more effective than prednisone/sirolimus/calcineurin-inhibitor for treating chronic graft-versus-host disease in treatment-naïve or early inadequate responders. Primary endpoints of this study were proportions of subjects alive without relapse or secondary therapy with 6-month complete or partial response in phase II, or with 2-year complete response in phase III. The prednisone/sirolimus/photopheresis arm closed prematurely because of slow accrual and the remaining two-drug versus three-drug study ended in phase II due to statistical futility with 138 evaluable subjects. The two-drug and three-drug arms did not differ in rates of 6-month complete or partial response (48.6% versus 50.0%, P=0.87), or 2-year complete response (14.7% versus 15.5%, P=0.90). Serum creatinine values >1.5 times baseline were less frequent in the calcineurin-inhibitor-free arm at 2 months (1.5% versus 11.7%, P=0.025) and 6 months (7.8% versus 24.0%, P=0.016). Higher adjusted Short Form-36 Physical Component Summary and Physical Functioning scores were seen in the two-drug arm at both 2 months (P=0.02 and P=0.04, respectively) and 6 months (P=0.007 and P=0.001, respectively). Failure-free survival and overall survival rates at 2 years were similar for patients in the the two-drug and three-drug arms (48.6% versus 46.2%, P=0.78; 81.5% versus 74%, P=0.28). Based on similar long-term outcomes, prednisone/sirolimus is a therapeutic alternative to prednisone/sirolimus/calcineurin-inhibitor for chronic graft-versus-host disease, being easier to administer and better tolerated. Clinicaltrials.gov identifier: NCT01106833.